Delineation of target expression profiles in CD341/CD382 and CD341/CD381 stem and progenitor cells in AML and CML

Harald Herrmann; Irina Sadovnik; Gregor Eisenwort; Thomas Rülicke; Katharina Blatt; Susanne Herndlhofer; Michael Willmann; Gabriele Stefanzl; Sigrid Baumgartner; Georg Greiner; Axel Schulenburg; Niklas Mueller; Werner Rabitsch; Martin Bilban; Gregor Hoermann; Berthold Streubel; Daniel A. Vallera; Wolfgang R. Sperr; Peter Valent

doi:10.1182/BLOODADVANCES.2020001742

Delineation of target expression profiles in CD34¹/CD38² and CD34¹/CD38¹ stem and progenitor cells in AML and CML

Harald Herrmann, Irina Sadovnik, Gregor Eisenwort, Thomas Rülicke, Katharina Blatt, Susanne Herndlhofer, Michael Willmann, Gabriele Stefanzl, Sigrid Baumgartner, Georg Greiner, Axel Schulenburg, Niklas Mueller, Werner Rabitsch, Martin Bilban, Gregor Hoermann, Berthold Streubel, Daniel A. Vallera, Wolfgang R. Sperr, Peter Valent

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n 5 274) or CML (n 5 97) and controls (n 5 288) for expression of cell membrane antigens on CD34¹/CD38² and CD34¹/CD38¹ cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD34¹/CD38² and CD34¹/CD38¹ cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD34¹/CD38² LSCs exhibited an almost invariable aberration profile, defined as CD25¹/CD26¹/CD56¹/CD93¹/IL-1RAP¹. By contrast, in patients with AML, CD34¹/CD38² cells variably expressed “aberrant” membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication–mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD34¹/CD38² LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.

Original language	English (US)
Pages (from-to)	5118-5132
Number of pages	15
Journal	Blood Advances
Volume	4
Issue number	20
DOIs	https://doi.org/10.1182/BLOODADVANCES.2020001742
State	Published - Oct 21 2020

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: P.V. received research grants from Celgene, Incyte, Domantis and Pfizer and honoraria from Celgene, Novartis, Incyte, Pfizer, Blueprint, and Deciphera. G.H. received research support from Novartis and honoraria from Novartis, Roche, Bristol-Myers Squibb, Pfizer, and Ariad. W.R.S. received honoraria and/or travel support from AbbVie, Amgen, Celgene, Daiichi Sankyo, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Teva. D.A.V. receives royalties and consulting honoraria from GT Biopharma. All conflicts have been managed by the University of Minnesota in conjunction with its conflict-of-interest policies. The remaining authors declare no competing financial interests.

Publisher Copyright:
© 2020 by The American Society of Hematology

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Herrmann, H., Sadovnik, I., Eisenwort, G., Rülicke, T., Blatt, K., Herndlhofer, S., Willmann, M., Stefanzl, G., Baumgartner, S., Greiner, G., Schulenburg, A., Mueller, N., Rabitsch, W., Bilban, M., Hoermann, G., Streubel, B., Vallera, D. A., Sperr, W. R., & Valent, P. (2020). Delineation of target expression profiles in CD34¹/CD38² and CD34¹/CD38¹ stem and progenitor cells in AML and CML. Blood Advances, 4(20), 5118-5132. https://doi.org/10.1182/BLOODADVANCES.2020001742

Herrmann, H, Sadovnik, I, Eisenwort, G, Rülicke, T, Blatt, K, Herndlhofer, S, Willmann, M, Stefanzl, G, Baumgartner, S, Greiner, G, Schulenburg, A, Mueller, N, Rabitsch, W, Bilban, M, Hoermann, G, Streubel, B, Vallera, DA, Sperr, WR & Valent, P 2020, 'Delineation of target expression profiles in CD34¹/CD38² and CD34¹/CD38¹ stem and progenitor cells in AML and CML', Blood Advances, vol. 4, no. 20, pp. 5118-5132. https://doi.org/10.1182/BLOODADVANCES.2020001742

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title = "Delineation of target expression profiles in CD341/CD382 and CD341/CD381 stem and progenitor cells in AML and CML",

abstract = "In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n 5 274) or CML (n 5 97) and controls (n 5 288) for expression of cell membrane antigens on CD341/CD382 and CD341/CD381 cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD341/CD382 and CD341/CD381 cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD341/CD382 LSCs exhibited an almost invariable aberration profile, defined as CD251/CD261/CD561/CD931/IL-1RAP1. By contrast, in patients with AML, CD341/CD382 cells variably expressed “aberrant” membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication–mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD341/CD382 LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.",

author = "Harald Herrmann and Irina Sadovnik and Gregor Eisenwort and Thomas R{\"u}licke and Katharina Blatt and Susanne Herndlhofer and Michael Willmann and Gabriele Stefanzl and Sigrid Baumgartner and Georg Greiner and Axel Schulenburg and Niklas Mueller and Werner Rabitsch and Martin Bilban and Gregor Hoermann and Berthold Streubel and Vallera, {Daniel A.} and Sperr, {Wolfgang R.} and Peter Valent",

note = "Funding Information: Conflict-of-interest disclosure: P.V. received research grants from Celgene, Incyte, Domantis and Pfizer and honoraria from Celgene, Novartis, Incyte, Pfizer, Blueprint, and Deciphera. G.H. received research support from Novartis and honoraria from Novartis, Roche, Bristol-Myers Squibb, Pfizer, and Ariad. W.R.S. received honoraria and/or travel support from AbbVie, Amgen, Celgene, Daiichi Sankyo, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Teva. D.A.V. receives royalties and consulting honoraria from GT Biopharma. All conflicts have been managed by the University of Minnesota in conjunction with its conflict-of-interest policies. The remaining authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",

year = "2020",

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day = "21",

doi = "10.1182/BLOODADVANCES.2020001742",

language = "English (US)",

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TY - JOUR

T1 - Delineation of target expression profiles in CD341/CD382 and CD341/CD381 stem and progenitor cells in AML and CML

AU - Herrmann, Harald

AU - Sadovnik, Irina

AU - Eisenwort, Gregor

AU - Rülicke, Thomas

AU - Blatt, Katharina

AU - Herndlhofer, Susanne

AU - Willmann, Michael

AU - Stefanzl, Gabriele

AU - Baumgartner, Sigrid

AU - Greiner, Georg

AU - Schulenburg, Axel

AU - Mueller, Niklas

AU - Rabitsch, Werner

AU - Bilban, Martin

AU - Hoermann, Gregor

AU - Streubel, Berthold

AU - Vallera, Daniel A.

AU - Sperr, Wolfgang R.

AU - Valent, Peter

N1 - Funding Information: Conflict-of-interest disclosure: P.V. received research grants from Celgene, Incyte, Domantis and Pfizer and honoraria from Celgene, Novartis, Incyte, Pfizer, Blueprint, and Deciphera. G.H. received research support from Novartis and honoraria from Novartis, Roche, Bristol-Myers Squibb, Pfizer, and Ariad. W.R.S. received honoraria and/or travel support from AbbVie, Amgen, Celgene, Daiichi Sankyo, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Teva. D.A.V. receives royalties and consulting honoraria from GT Biopharma. All conflicts have been managed by the University of Minnesota in conjunction with its conflict-of-interest policies. The remaining authors declare no competing financial interests. Publisher Copyright: © 2020 by The American Society of Hematology

PY - 2020/10/21

Y1 - 2020/10/21

N2 - In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n 5 274) or CML (n 5 97) and controls (n 5 288) for expression of cell membrane antigens on CD341/CD382 and CD341/CD381 cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD341/CD382 and CD341/CD381 cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD341/CD382 LSCs exhibited an almost invariable aberration profile, defined as CD251/CD261/CD561/CD931/IL-1RAP1. By contrast, in patients with AML, CD341/CD382 cells variably expressed “aberrant” membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication–mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD341/CD382 LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.

AB - In an attempt to identify novel markers and immunological targets in leukemic stem cells (LSCs) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened bone marrow (BM) samples from patients with AML (n 5 274) or CML (n 5 97) and controls (n 5 288) for expression of cell membrane antigens on CD341/CD382 and CD341/CD381 cells by multicolor flow cytometry. In addition, we established messenger RNA expression profiles in purified sorted CD341/CD382 and CD341/CD381 cells using gene array and quantitative polymerase chain reaction. Aberrantly expressed markers were identified in all cohorts. In CML, CD341/CD382 LSCs exhibited an almost invariable aberration profile, defined as CD251/CD261/CD561/CD931/IL-1RAP1. By contrast, in patients with AML, CD341/CD382 cells variably expressed “aberrant” membrane antigens, including CD25 (48%), CD96 (40%), CD371 (CLL-1; 68%), and IL-1RAP (65%). With the exception of a subgroup of FLT3 internal tandem duplication–mutated patients, AML LSCs did not exhibit CD26. All other surface markers and target antigens detected on AML and/or CML LSCs, including CD33, CD44, CD47, CD52, CD105, CD114, CD117, CD133, CD135, CD184, and roundabout-4, were also found on normal BM stem cells. However, several of these surface targets, including CD25, CD33, and CD123, were expressed at higher levels on CD341/CD382 LSCs compared with normal BM stem cells. Moreover, antibody-mediated immunological targeting through CD33 or CD52 resulted in LSC depletion in vitro and a substantially reduced LSC engraftment in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. Together, we have established surface marker and target expression profiles of AML LSCs and CML LSCs, which should facilitate LSC enrichment, diagnostic LSC phenotyping, and development of LSC-eradicating immunotherapies.

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